tbuckley/cabot-search huggingface dataset:
Abstract 14980: Enhanced External Counterpulsation Improves Cognitive Function in Long Covid Patients
Authors: Mohanakrishnan Sathyamoorthy, Rajkumar Sevak, Monica Verduzco-Gutierrez, Juan Cabrera, Marielisa Lopez, Sachin A Shah
Journal: Circulation (2022)

INTRODUCTION: Enhanced External Counterpulsation (EECP) has been described to help Long Covid related cardiovascular (e.g. chest pain, fatigue) and neurocognitive (e.g. brain fog) symptoms. We sought to determine whether EECP improves cognitive function. Methods: A retrospective evaluation of a contemporary consecutive patient cohort referred to Flow Therapy for management of Long Covid. All patients subjectively reporting brain fog were assessed using the BrainCheck tool to determine degree of cognitive impairment pre- and post EECP therapy. BrainCheck is an FDA-approved, web-based battery of standardized neuropsychological tests that includes the Trail Making Test (Trails A, Trails B) for assessing executive function (cognitive flexibility), the Digit Symbol Substitution Test (DSST) for assessing attention and processing speed, the Stroop Test for assessing executive function (response inhibition), and the List Learning Test for immediate/delayed verbal memory evaluation. BrainCheck scores have a normative mean of 100±15 with a clinically meaningful change ranging from 12-21 depending on age. Change from baseline to post-EECP were assessed using the paired student’s t-test. Results: A total of 51 Long Covid patients were included (49.3±11.0 years, 60.8% female, 22% had CAD) with the average duration since Covid diagnosis being 9.9±6.1months. No patients were excluded. All patients completed 25-35 sessions of EECP. Baseline BrainCheck composite score was 88.0±22.1 which significantly improved to 100.1±16.4 post-EECP (+11.9±18.7, p&lt;0.001). When limiting to baseline score under 85 (n=20; baseline average 66.7±17.6) the improvement was +26.0±20.9 (p&lt;0.001). EECP therapy improved the patients’ performance across cognitive domains, as indicated by significant enhancements in scores from baseline in Trails A (+6.1±19.7), Trails B (+5.0±11.8), DSST (+12.9±24.1) and Stroop Test (+11.2±19.1) (all p-values&lt;0.05). Conclusion: This is the first evaluation showing significant improvement in Long Covid related cognitive impairment post-EECP therapy. Further study is needed to determine if the mechanistic basis may include EECP induced improved cerebral perfusion, change in endothelial function, or a yet unelucidated pathway.
Abstract 13558: Opening the Black Box of Artificial Intelligence: Visualization of Detecting Heart Failure Subtypes Using Electrocardiography
Authors: Hak Seung Lee, Jong-Hwan Jang, Sora Kang, Yong-Yeon Jo, Jeong Min Son, Min Sung Lee, Joon-Myoung Kwon
Journal: Circulation (2022)

Objectives: To evaluate and visualize how artificial intelligence (AI) recognizes electrocardiography (ECG) characteristics of each heart failure (HF) subtype. We developed a visually explainable and interpretable AI-ECG algorithm for various HF subtypes to meet this need. This study proposes the ShapeExplainer (SE) to interpret models. Methods: From 33,920 patients at two hospitals, we trained a convolutional neural network to identify patients with HF subtypes using ECG and clinical diagnosis. HF subtypes include heart failure with reduced ejection fraction (HFrEF), heart failure with mid-range ejection fraction (HFmrEF, and heart failure with preserved ejection fraction (HFpEF) ( Figure a ). To interprete each HF classifier model, SE, which converts non-HF group data to be recognized as each HF subtype by each classifier, was trained. The converted fake ECG shows what the change is for the classifier to recognize as each HF subtype. SE from the non-HF group of the external validation set shows the result by comparing the shape before and after transformation. Results: When tested on an independent set of 6,784 patients, the network model yielded values for the area under the curves of HFrEF of 0.945, HFmrEF of 0.884, and HFpEF of 0.859, respectively. The results of each classifier were visualized by overlapping the original and newly generated ECGs. Comparing each subtype and its fake ECG, there was no clear trend of electrocardiographic features. However, fake ECG showed a tendency of qrs amplitude as it progressed to non-HF, HFpEF, HFmrEF, and HFrEF, especially in T wave or ST-change ( Figure b ). Conclusions: The proposed fake ECG generating method is a new approach for interpreting the AI-ECG model, helping physicians understand how AI recognizes HF subtypes.
Abstract 14970: Early Observations of Population Characteristics for an Electrocardiogram-Enabled Smartwatch in the United States
Authors: Hannah Truong, Nandini Nayar, Aniket Zinzuwadia, Noor Osman, Jana Goldberg, Mark Hanson, Jeff Wessler
Journal: Circulation (2022)

Introduction: Over one-in-five Americans now use a smartwatch or fitness tracker and many wearables now offer electrocardiogram (ECG) capabilities. Expert interpretation of single-lead ECGs has demonstrated high diagnostic accuracy in atrial fibrillation (AF) detection, suggesting potential as a screening tool. Generalizability concerns remain given limited available data on age and geographic distributions of consumer smartwatch users. Methods: After obtaining FDA clearance, consumer smartwatch was launched in the United States in November 2021 and enabled users to transmit single-lead ECG recordings. Between November 2021 and May 2022, Heartbeat Health, a team with trained virtual cardiology providers, received and interpreted ECG recordings from 13,915 smartwatch users. Each reading was classified into five categories: 1) atrial fibrillation 2) normal sinus rhythm 3) high heart rate 4) low heart rate 5) possible other arrhythmia and 6) artifact. ECG findings were categorized by age and state Bloomberg Innovation Index (BII) for population analysis. Results: Of the 13,915 patients (average age 48.8 years) included in the analysis, 84.4% were under age 65 with an AF prevalence of 0.3%, and 15.1% of patients were over age 65 with an AF prevalence of 3.6%. States with higher innovation quintiles were associated with a higher share of users and users younger in age. Around 35.9% of our user population belonged to states in the first BII quintile but states in the first quintile only account for 25.6% of the total US population. Conclusions: Characterization of smartwatch ECG users revealed a higher share of users and younger users in states with higher BII, measured by density of technology companies, research &amp; development, and postsecondary education. A large-scale trained provider review of smartwatch-enabled ECGs revealed rates of AF that were lower than the widely understood prevalence of AF in the US, suggestive of a potential demographic gap between consumers with access versus those that are more likely to surface undiagnosed AF via smartwatch ECG screening. With the growing penetration of consumer smartwatches, equitable distribution of innovation is increasingly important.
Abstract 14995: Outcomes of Transcatheter Aortic Valve Replacements in Patients With Left Ventricular Assist Device
Authors: Dhrubajyoti Bandyopadhyay, Aaqib H Malik, Akshay Goel, Rahul Gupta, Ravi Shah, Adrija Hajra, HASAN AHMAD
Journal: Circulation (2022)

Background: The development or progression of aortic insufficiency (AI) to moderate to severe in patients with left ventricular assist devices (LVADs) for end stage heart failure has been increasingly recognized and occurs in 30-40% of patients with continuous flow LVADs. This can lead to reduced efficiency of the LVAD and is associated with increased rates of hospitalizations and mortality. Up to 30% of LVAD patients with moderate to severe AI require surgical valve closure or replacement, which is high risk. More recently, case reports demonstrated transcatheter aortic valve replacement (TAVR) is feasible in LVAD patients with symptomatic AI, but there is a lack of large-scale study. Methods: National Readmission Databases (NRD) from 2015 to 2019 were used to identify hospitalizations with International Classification of Diseases-9th Revision and International Classification of Diseases-10th Revision procedural codes for TAVR in patients with and without LVAD. The outcomes of interest were mortality and 30-day readmission rate. Results: We identified a total of 245,176 TAVR hospitalizations. Among them, 146 (0.001%) had LVAD. LVAD patients undergoing TAVR were significantly younger (mean age 67.5 years vs. 79.6 years; P: &lt;0.001) and had more comorbidities such as arrhythmias, peripheral vascular disease, chronic kidney disease, and anemia. On univariate analysis, LVAD patients demonstrated higher mortality (OR 4.88; 95% CI 2.17 - 11.02; P: &lt;0.001), however, multivariate analysis showed this trend to be insignificant (OR 1.91; 95% CI 0.74-4.96; P= 0.184). Overall, patients with LVAD undergoing TAVR did have an increased length of stay and higher cost of hospitalization (P&lt;0.001). We have witnessed the increasing trend of TAVR use in LVAD patients in the last five years (P: 0.009). After the propensity match, the 30-day readmission rate was not statistically significant (26.5 vs. 25%, P: 0.84). Conclusion: In our analysis, the mortality and 30-day readmission of LVAD patients undergoing TAVR were not significantly higher compared to non-LVAD patients. However, this finding may be limited due to the relatively small number of patients. Overall, this study indicates that TAVR may be considered in the appropriately selected LVAD patients.
Abstract 14942: Neurovascular Injury in a Mini-Swine Model of Recanalized Acute Ischemic Stroke
Authors: Joaquim Bobi, Aladdin Taha, Victor Volovici, Jadey D Raben, Romy van Noort, Mathijs Stam, Dirk J Duncker, Ruben Dammers, Diederik W Dippel, Heleen M Van Beusekom
Journal: Circulation (2022)

Background, hypothesis: Gyrencephalic large-animal models of acute ischemic stroke (AIS) such as swine gain attention in translating preclinical to clinical stroke research, with brain anatomy similar to humans. Most swine models employ young animals with AIS by permanent occlusion (P-AIS). This does not reflect the, often elderly, stroke patient. Therefore, recanalized AIS (R-AIS) in adult mini-pigs could improve preclinical to clinical translation. Methods: Anesthetized adult (2 yrs) Aachen mini-pigs (n=6) underwent craniotomy to occlude right-side middle cerebral arteries (MCA) with aneurysm clips. Clips were released at 4 hrs to allow recanalization for 2-4 hrs (R-AIS, n=4) or left in place until sacrifice (P-AIS, n=1). 3D angiography confirmed occlusion and recanalization. Infarct size was determined by TTC staining and expressed as % infarct per hemisphere (median, min-max). Qualitative neurovascular histology was performed in HE-stained sections of ischemic and remote (contralateral) tissue. Results: All animals survived until end-of-procedure. In 4 of 5 animals R-AIS successfully induced cortical infarcts (infarct size, 16.2% [9.1%-25.2%]). R-AIS was unsuccessful in 1 animal, with a small striatum infarct (2.7%) without cortical involvement and unclear angiographic occlusion. P-AIS (n=1) resulted in 12.7% infarct. Assessment of ischemic (TTC-neg) tissue revealed characteristic histology of ischemia/reperfusion-derived neurovascular damage, including erythrocyte extravasation, vasostasis, increased perivascular space and intravascular platelet/fibrin aggregates ( Figure 1 ) in all animals. Remote tissue did not show any of these features. Conclusions: Adult Aachen mini-pigs can be used for acute ischemic stroke modelling and display characteristic neurovascular features associated with ischemia and reperfusion. They may serve as a model for translational therapeutic neuro(vascular)-protective research.
Abstract 14978: Association Between Microvascular Dysfunction and Heart Failure Related Outcomes in Ischemia With Non-Obstructive Coronary Arteries Based on a Novel Angiography-Derived Index
Authors: Ka Lam Calvin Leung, Lok Yee Lam, Kwan Yu LI, Tse Yi Kei Stephanie, Shuk Yin Yu, Yundi Feng, Yunlong Huo, Hung Fat Tse, Kai Hang Yiu
Journal: Circulation (2022)

Introduction: Coronary angiography-derived index of microvascular resistance (caIMR) is a index that quantifies coronary microvascular dysfunction (CMD), which obviates the need of wire manipulation compared to index of microvascular resistance (IMR). In patients with ischemia with non-obstructive coronary arteries (INOCA), CMD plays a key role and is associated with development of heart failure (HF). The significance of global CMD, reflected by the average of caIMR values obtained in the three coronary arteries was however not fully known. The aim of this study was to evaluate the association between HF related outcomes (HFRO) and global CMD in INOCA patients based on caIMR. Methods: Patients with clinical myocardial ischemia and without ≥50% diameter stenosis in any coronary arteries on coronary angiography were included. For every patient, the global-caIMR value was calculated by averaging caIMR values measured in the three major coronary arteries, and it reflects the extent of global CMD. Based on IMR threshold, patients were stratified into high-global-caIMR group (global-caIMR≥25U) and low-global-caIMR group (global-caIMR&lt;25U). The primary endpoint was HFRO, defined by a composite of HF related hospitalization and outpatient diuretic intensification. Results: Among 325 patients included (mean age 63.4±11.0; male 57.2%), 105 and 220 patients were stratified into the high- and low-global-caIMR groups respectively. The rate of HFRO at 3 years was higher in the high-global-caIMR group compared to low-global-caIMR group (19.0% vs. 8.2%; P=0.004). In multivariable analysis adjusted for age, gender, Charlson Comorbidity Index and baseline HF, global-caIMR≥25U was associated with a higher risk of HFRO at 3 years (subdistribution hazard ratio [sHR], 2.65; 95% confidence interval [CI], 1.39-5.06; P=0.003). With the same multivariable adjustment, every 1U increase in global-caIMR was associated with an increased risk of HFRO at 3 years (sHR, 1.07; 95% CI, 1.05-1.09; P&lt;0.001). Similar trends were observed at 5 years of follow-up. Conclusions: Global CMD, reflected by increased global-caIMR, was associated with a higher risk of HFRO at 3 and 5 years in INOCA patients. This study provides clinical data that support real-world application of caIMR.
Clinical and biochemical impact of vitamin B6 deficiency in primary sclerosing cholangitis before and after liver transplantation
Authors: Peder Rustøen Braadland, Annika Bergquist, Martin Kummen, Lars Bossen, Lise Katrine Engesæter, Henrik Mikael Reims, Ida Björk, Krzysztof Grzyb, Andreas Abildgaard, Milada Cvancarova Småstuen, Trine Folseraas, Marius Trøseid, Arve Ulvik, Per Magne Ueland, Espen Melum, Pål-Dag Line, Marte Lie Høivik, Henning Grønbæk, Tom Hemming Karlsen, Mette Vesterhus, Johannes Roksund Hov
Journal: Journal of Hepatology (2023)

We previously demonstrated that people with primary sclerosing cholangitis (PSC) had reduced gut microbial capacity to produce active vitamin B6 (pyridoxal 5'-phosphate [PLP]), which corresponded to lower circulating PLP levels and poor outcomes. Here, we define the extent and biochemical and clinical impact of vitamin B6 deficiency in people with PSC from several centers before and after liver transplantation (LT).We used targeted liquid chromatography-tandem mass spectrometry to measure B6 vitamers and B6-related metabolic changes in blood from geographically distinct cross-sectional cohorts totaling 373 people with PSC and 100 healthy controls to expand on our earlier findings. Furthermore, we included a longitudinal PSC cohort (n = 158) sampled prior to and serially after LT, and cohorts of people with inflammatory bowel disease (IBD) without PSC (n = 51) or with primary biliary cholangitis (PBC) (n = 100), as disease controls. We used Cox regression to measure the added value of PLP to predict outcomes before and after LT.In different cohorts, 17-38% of people with PSC had PLP levels below the biochemical definition of a vitamin B6 deficiency. The deficiency was more pronounced in PSC than in IBD without PSC and PBC. Reduced PLP was associated with dysregulation of PLP-dependent pathways. The low B6 status largely persisted after LT. Low PLP independently predicted reduced LT-free survival in both non-transplanted people with PSC and in transplant recipients with recurrent disease.Low vitamin B6 status with associated metabolic dysregulation is a persistent feature of PSC. PLP was a strong prognostic biomarker for LT-free survival both in PSC and recurrent disease. Our findings suggest that vitamin B6 deficiency modifies the disease and provides a rationale for assessing B6 status and testing supplementation.We previously found that people with PSC had reduced gut microbial potential to produce essential nutrients. Across several cohorts, we find that the majority of people with PSC are either vitamin B6 deficient or have a marginal deficiency, which remains prevalent even after liver transplantation. Low vitamin B6 levels strongly associate with reduced liver transplantation-free survival as well as deficits in biochemical pathways dependent on vitamin B6, suggesting that the deficiency has a clinical impact on the disease. The results provide a rationale for measuring vitamin B6 and to investigate whether vitamin B6 supplementation or modification of the gut microbial community can help improve outcomes for people with PSC.
GPRC5D-Targeted CAR T Cells for Myeloma.
Authors: Sham Mailankody, Sean M Devlin, Jonathan Landa, Karthik Nath, Claudia Diamonte, Elizabeth J Carstens, Douglas Russo, Romany Auclair, Lisa Fitzgerald, Briana Cadzin, Xiuyan Wang, Devanjan Sikder, Brigitte Senechal, Vladimir P Bermudez, Terence J Purdon, Kinga Hosszu, Devin P McAvoy, Tasmin Farzana, Elena Mead, Jessica A Wilcox, Bianca D Santomasso, Gunjan L Shah, Urvi A Shah, Neha Korde, Alexander Lesokhin, Carlyn R Tan, Malin Hultcrantz, Hani Hassoun, Mikhail Roshal, Filiz Sen, Ahmet Dogan, Ola Landgren, Sergio A Giralt, Jae H Park, Saad Z Usmani, Isabelle Rivière, Renier J Brentjens, Eric L Smith
Journal: New England Journal of Medicine (2022)

B-cell maturation antigen (BCMA)-directed chimeric antigen receptor (CAR) T-cell therapies have generated responses in patients with advanced myeloma, but relapses are common. G protein-coupled receptor, class C, group 5, member D (GPRC5D) has been identified as an immunotherapeutic target in multiple myeloma. Preclinical studies have shown the efficacy of GPRC5D-targeted CAR T cells, including activity in a BCMA antigen escape model.In this phase 1 dose-escalation study, we administered a GPRC5D-targeted CAR T-cell therapy (MCARH109) at four dose levels to patients with heavily pretreated multiple myeloma, including patients with relapse after BCMA CAR T-cell therapy.A total of 17 patients were enrolled and received MCARH109 therapy. The maximum tolerated dose was identified at 150×106 CAR T cells. At the 450×106 CAR T-cell dose, 1 patient had grade 4 cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome (ICANS), and 2 patients had a grade 3 cerebellar disorder of unclear cause. No cerebellar disorder, ICANS of any grade, or cytokine release syndrome of grade 3 or higher occurred in the 12 patients who received doses of 25×106 to 150×106 cells. A response was reported in 71% of the patients in the entire cohort and in 58% of those who received doses of 25×106 to 150×106 cells. The patients who had a response included those who had received previous BCMA therapies; responses were observed in 7 of 10 such patients in the entire cohort and in 3 of 6 such patients who received 25×106 to 150×106 cells.The results of this study of a GPRC5D-targeted CAR T-cell therapy (MCARH109) confirm that GPRC5D is an active immunotherapeutic target in multiple myeloma. (Funded by Juno Therapeutics/Bristol Myers Squibb; ClinicalTrials.gov number, NCT04555551.).
Synergising single-cell resolution and 4sU labelling boosts inference of transcriptional bursting
Authors: David M. Edwards, Philip Davies, Daniel Hebenstreit
Journal: Genome biology (2023)

Despite the recent rise of RNA-seq datasets combining single-cell (sc) resolution with 4-thiouridine (4sU) labelling, analytical methods exploiting their power to dissect transcriptional bursting are lacking. Here, we present a mathematical model and Bayesian inference implementation to facilitate genome-wide joint parameter estimation and confidence quantification (R package: burstMCMC). We demonstrate that, unlike conventional scRNA-seq, 4sU scRNA-seq resolves temporal parameters and furthermore boosts inference of dimensionless parameters via a synergy between single-cell resolution and 4sU labelling. We apply our method to published 4sU scRNA-seq data and linked with ChIP-seq data, we uncover previously obscured associations between different parameters and histone modifications.
Controlling release from encapsulated drug-loaded devices: insights from modeling the dissolution front propagation
Authors: Ankur Jain, David King, Giuseppe Pontrelli, Sean McGinty
Journal: Journal of Controlled Release (2023)

Dissolution of drug from its solid form to a dissolved form is an important consideration in the design and optimization of drug delivery devices, particularly owing to the abundance of emerging compounds that are extremely poorly soluble. When the solid dosage form is encapsulated, for example by the porous walls of an implant, the impact of the encapsulant drug transport properties is a further confounding issue. In such a case, dissolution and diffusion work in tandem to control the release of drug. However, the interplay between these two competing processes in the context of drug delivery is not as well understood as it is for other mass transfer problems, particularly for practical controlled-release considerations such as an encapsulant layer around the drug delivery device. To address this gap, this work presents a mathematical model that describes controlled release from a drug-loaded device surrounded by a passive porous layer. A solution for the drug concentration distribution is derived using the method of eigenfunction expansion. The model is able to track the dissolution front propagation, and predict the drug release curve during the dissolution process. The utility of the model is demonstrated through comparison against experimental data representing drug release from a cylindrical drug-loaded orthopedic fixation pin, where the model is shown to capture the data very well. Analysis presented here reveals how the various geometrical and physicochemical parameters influence drug dissolution and, ultimately, the drug release profile. It is found that the non-dimensional initial concentration plays a key role in determining whether the problem is diffusion-limited or dissolution-limited, whereas the nature of the problem is largely independent of other parameters including diffusion coefficient and encapsulant thickness. We expect the model will prove to be a useful tool for those designing encapsulated drug delivery devices, in terms of optimizing the design of the device to achieve a desired drug release profile.